tbuckley/cabot-search huggingface dataset:
Follicular Lymphoma Microenvironment Characteristics Associated with Tumor Cell Mutations and MHC Class II Expression
Authors: Guangchun Han, Qing Deng, Mario L. Marques-Piubelli, Enyu Dai, Minghao Dang, Man Chun John Ma, Xubin Li, Haopeng Yang, Jared Henderson, Olga Kudryashova, Mark Meerson, Sergey Isaev, Nikita Kotlov, Krystle J. Nomie, Alexander Bagaev, Edwin R. Parra, Luisa M. Solis Soto, Simrit Parmar, Fredrick B. Hagemeister, Sairah Ahmed, Swaminathan P. Iyer, Felipe Samaniego, Raphael Steiner, Luis Fayad, Hun Lee, Nathan H. Fowler, Christopher R. Flowers, Paolo Strati, Jason R. Westin, Sattva S. Neelapu, Loretta J. Nastoupil, Francisco Vega, Linghua Wang, Michael R. Green
Journal: Blood Cancer Discovery (2022)

Abstract Follicular lymphoma (FL) is a B-cell malignancy with a complex tumor microenvironment that is rich in nonmalignant immune cells. We applied single-cell RNA sequencing to characterize the diverse tumor and immune cell populations of FL and identified major phenotypic subsets of FL T cells, including a cytotoxic CD4 T-cell population. We characterized four major FL subtypes with differential representation or relative depletion of distinct T-cell subsets. By integrating exome sequencing, we observed that somatic mutations are associated with, but not definitive for, reduced MHC expression on FL cells. In turn, expression of MHCII genes by FL cells was associated with significant differences in the proportions and targetable immunophenotypic characteristics of T cells. This provides a classification framework of the FL microenvironment in association with FL genotypes and MHC expression, and informs different potential immunotherapeutic strategies based upon tumor cell MHCII expression. Significance: We have characterized the FL-infiltrating T cells, identified cytotoxic CD4 T cells as an important component that is associated with tumor cell–intrinsic characteristics, and identified sets of targetable immune checkpoints on T cells that differed from FLs with normal versus low MHC expression. See related commentary by Melnick, p. 374. This article is highlighted in the In This Issue feature, p. 369
Abstract 3349: In-silico analysis identifies the unique role of the ADRB2-USP20 axis in T cell lymphoma
Authors: Rajan Kumar Tiwari, Ajay Kumar
Journal: Cancer Research (2022)

Abstract T cell lymphoma represents an aggressive subgroup of lymphoma having a poor prognosis. Many factors, including psychological stress, define the onset/progression of the disease. Although psychological stress can cause several health problems, preclinical and clinical reports regarding its role in cancer have been mixed. Therefore, in this study, we sought to determine the role of psychological stress hormone in the progression of T cell lymphoma and provide a mechanistic framework of activity. Initially, we used the cBioportal and performed expression analysis of genes involved in stress pathways with large-scale cancer genomics TCGA datasets having nearly 10071 patient samples. Through a series of in-silico investigations, we identified Adrenoceptor Beta 2 (ADRB2), a key mediator of stress, highly expressed in T cell lymphoma compared to other tumors.Furthermore, the expression of ADRB2 was not gender-specific and equally represented in both males and females. String analysis further identified the interaction of ADRB2 with Ubiquitin carboxyl-terminal hydrolase 20 (USP20), which directly regulates Hypoxia-inducible factor 1-alpha (HIF1-A) and ADRB2. This regulation could lead to enhanced glucose metabolism to support T cell lymphoma growth and progression. Collectively, our in-silico findings suggest that psychological stress releases hormones that could modulate T cell lymphoma proliferation through the ADRB2-USP20 axis. Ongoing preclinical studies with stress hormones will be presented to provide undescribed mechanisms of their protumorigenic activity through the ADRB2-USP20 axis and their role in regulating cancer-specific metabolism. We sought to determine the role of psychological stress hormone These studies will provide an opportunity to learn the involvement of stress hormones in cancer progression and provide a framework for developing a novel approach for stress management during cancer. Citation Format: Rajan Kumar Tiwari, Ajay Kumar. In-silico analysis identifies the unique role of the ADRB2-USP20 axis in T cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3349.
Abstract 1457: NELFE regulates chromatin accessibility to affect MYC induced transcription
Authors: Kai Zhang, Anna Barry, Ryan Lamm, Hien Dang
Journal: Cancer Research (2022)

Abstract Liver cancer incidence rates have more than tripled in the last 40 years and is projected to increase more than 40% in the next decade. Although progress has been made, there is still limited therapeutic options. Due to the various etiological factors associated in HCC development and late stage in which it is diagnosed, the five-year survival rate is only 20%. Molecularly, more than 80% of HCC has an alteration in MYC signaling. Yet, MYC remains undruggable and studies over the recent years show that targeting proteins that regulate MYC is a promising approach in developing anti-cancer therapies. One such protein is the RNA binding protein (RBP) Negative Elongation Factor E (NELFE). We recently demonstrated for the first-time that NELFE recruits MYC via protein-protein interactions to the chromatin to control the expression of pro-survival genes. Consistent with the role of NELFE as a regulator of MYC in these cancers, we showed that patients with aberrant NELFE expression concurrently have active MYC signaling and poor outcome. These studies suggest that the NELFE/MYC interplay may be important for HCC maintenance. Thus, our hypothesis is that NELFE modulates the chromatin landscape to facilitate MYC-induced transcription to promote HCC. To investigate NELFE’s effect on MYC-induced transcription, we performed NELFE and MYC ChIP-sequencing and ATAC-sequencing analyses on CRISPR/Cas9-mediated NELFE knockout HCC cells. We found NELFE depletion resulted in significant reduction in nucleosomal accessibility and MYC binding to the chromatin near promoter-proximal regions. Although NELFE depletion alters the chromatin landscape, we found it rarely interacts with the chromatin, specifically within MYC bound regions, suggesting that the MYC/NELFE interaction is facilitated by a third protein. NELFE co-immunoprecipitation followed by mass spectrometry analyses identified the protein SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily B, Member 1 (SMARCB1) as a potential MYC cofactor that facilitates the NELFE/MYC interaction. Immunoblotting analyses show NELFE interacts with SMARCB1 and MYC and loss of NELFE significantly reduced SMARCB1/MYC interactions, indicating that NELFE facilitates chromatin accessibility through SMARCB1, which is required for MYC-induced transcription. Future studies include investigating SMARCB1’s oncogenic role in HCC through NELFE/MYC signaling. Citation Format: Kai Zhang, Anna Barry, Ryan Lamm, Hien Dang. NELFE regulates chromatin accessibility to affect MYC induced transcription [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1457.
Abstract LB549: LncRNA PCAT1 activates SOX2 and suppresses radioimmune responses via regulating cGAS/STING signaling in non-small cell lung cancer
Authors: Yanping Gao, Nannan Zhang, Yan Gong, Conghua Xie
Journal: Cancer Research (2022)

Abstract Background: The long non-coding RNA (lncRNA) PCAT1 is upregulated in non-small cell lung cancer (NSCLC), and promotes tumor growth and metastasis, but its roles in the radioimmune responses remain unknown. We aimed to investigate the impacts of PCAT1 on tumorigenesis and radioimmune responses and the underlying molecular mechanisms in NSCLC. Methods: Comprehensive bioinformatics analysis was performed to identify immunosuppressive lncRNAs involved with tumor invasion in NSCLC. The expression levels of PCAT1 were analyzed by in situ hybridization in 55 paired NSCLC and adjacent normal tissues. Both loss- and gain-of-function assays were performed to evaluate the functions of PCAT1 and SOX2 in NSCLC cell behaviors in vivo and in vitro. Bioinformatic analyses, chromatin isolation by RNA purification and dual-luciferase reporter assays were applied to validate the regulatory effects of PCAT1 on SOX2 expression. Chromatin immunoprecipitation, luciferase, and rescue assays were utilized to identify the relationship between SOX2 and the cGAS/STING signaling. Results: PCAT1 was immunosuppressive and related with NSCLC invasion. Increased PCAT1 was negatively correlated with immune cell infiltration in NSCLC. PCAT1 knockdown restrained proliferation, increased apoptosis, and inhibited cell migration and invasion in vivo and in vitro. PCAT1 activated SOX2 that accelerated tumorigenesis and immunosuppression. SOX2 promoted tumor growth through inhibiting cytotoxic T cell immunity. Moreover, SOX2 restrained cGAS transcription and hampered downstream type I IFN-induced immune responses. Inhibition of PCAT1/SOX2 in collaboration with radiation further inhibited tumor growth, and activated the cGAS/STING signaling pathway, which enhanced the immune responses of radiotherapy in NSCLC. Conclusions: PCAT1/SOX2 axis promoted tumorigenesis and immunosuppression through inhibition of cGAS/STING signaling-mediated T-cell activation. Inhibition of PCAT1 and SOX2 synergized with radiotherapy to activate the immune response and could serve as potential therapeutic targets. Citation Format: Yanping Gao, Nannan Zhang, Yan Gong, Conghua Xie. LncRNA PCAT1 activates SOX2 and suppresses radioimmune responses via regulating cGAS/STING signaling in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB549.
Cefepime population pharmacokinetics and dosing regimen optimization in critically ill children with different renal function
Authors: Noémie de Cacqueray, Déborah Hirt, Yi Zheng, Emmanuelle Bille, Pierre Louis Leger, Jérôme Rambaud, Julie Toubiana, Anais Chosidow, Sophie Vimont, Delphine Callot, Laurent Chouchana, Agathe Béranger, Jean Marc Tréluyer, Sihem Benaboud, Mehdi Oualha
Journal: Clinical Microbiology and Infection (2022)
Abstract 3639: Senescent stromal cells drive breast cancer tumorigenesis
Authors: Jiayu (Jennifer) Ye, Ana Paula Delgado, Scott Powers, Sheila Stewart
Journal: Cancer Research (2022)

Abstract Age is the largest risk factor for the development of cancer, including breast cancer, which is the most frequent malignancy in women. Investigation into how age impacts breast cancer development suggests that both the accumulation of oncogenic mutations within incipient tumor cells and age-related stromal changes conspire to drive tumorigenesis. While numerous physiologic changes arise with age, we posit that the accumulation of p16INKA4 (p16) positive senescent cells, which express various cytokines, chemokines, and enzymes collectively referred to as the senescence-associated secretory phenotype (SASP) contribute to cancer progression. SASP factors not only directly promote the proliferation of tumor cells, but also create an immunosuppressive microenvironment that contributes to robust tumor growth. Immunosuppressive SASP factors are detectable in human breast cancer stroma and high p16 positivity in stromal cells strongly correlates with breast cancer recurrence regardless of subtype. To investigate the role of senescent stroma in mammary tumor development, we crossed MMTV-PyMT (PyMT) transgenic mice that spontaneously develop mammary tumors to INK-ATTAC (INK) mice, which allows selective elimination of p16-positive cells. Depletion of senescent stromal cells in PyMT/INK mice led to significantly delayed mammary tumor onset and changes in various tumor-infiltrating immune cell populations. Analyses of single-cell RNA-sequencing (scRNA-seq) datasets of murine and human mammary tumor/breast cancer samples revealed that senescence is restricted to a cancer-associated fibroblasts (CAFs) subpopulation, which expresses high levels of immune-related and extracellular matrix (ECM)-related SASP factors and shows decreasing abundance in PyMT/INK mice upon the depletion of senescent stroma. Together, these data suggest that senescent CAFs contribute to mammary gland tumorigenesis by modulating tumor immunity and remodeling ECM in the microenvironment. Citation Format: Jiayu (Jennifer) Ye, Ana Paula Delgado, Scott Powers, Sheila Stewart. Senescent stromal cells drive breast cancer tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3639.
Abstract 5031: Improved deconvolution of combined bulk and single-cell RNA-sequencing data
Authors: Haoyun Lei, Xiaoyan A. Guo, Yifeng Tao, Kai Ding, Xuecong Fu, Steffi Oesterreich, Adrian V. Lee, Russell Schwartz
Journal: Cancer Research (2022)

Abstract Identifying how cell types and their abundances evolve during tumor progression is critical to understanding the mechanisms and identifying predictors of metastasis. Single-cell RNA sequencing (scRNA-seq) has been especially promising in resolving heterogeneity of expression programs at the single cell level but is not always available, for example for large cohort studies or longitudinal analysis of archived samples. In such cases, cell subpopulations must be inferred by deconvolution, a process that can infer single-cell genomic data from bulk data but has limited ability to resolve fine clonal structure. We extend our previous bulk genomic deconvolution tool, Robust and Accurate Deconvolution (RAD), to establish a new method, scRAD, that can use reference scRNA-seq to interpret sample collections for which only bulk RNA-seq is available for some samples, e.g., clonally resolving archived primary (PRM) tissues using scRNA-seq from metastases (METs). We preprocess scRNA-seq data to accurately represent gene expression profiles, yielding a signature matrix S then extend our RAD method via a regularization term to deconvolve bulk data while maximizing consistency with S. We validate our method on semi-synthetic data derived from human PRM breast cancer cases and bone and ovary METs, showing that scRAD improves inference of single-cell gene expression profiles and their frequencies relative to the prior RAD with random initialization or initialization using the single-cell matrix S (Table 1). We then apply scRAD to a collection of paired PRM and MET tumors to quantify progression changes in common cell types. One-sided Kaplan-Meier analysis shows that tumors inferred to increase the mast cell fraction from PRM to MET exhibit lower overall survival (p&amp;lt;0.05), consistent with the role of mast cells in metastatic growth and propagation. Tumors that show increased macrophage cell fraction from PRM to MET show improved overall survival (p&amp;lt;0.04), consistent with the role of immune infiltration in survival. mean square error (MSE) of gene expression and mixture fraction inference on semi-simulated data Method RAD with random initialization RAD with random initialization RAD with random initialization RAD initialized with S RAD initialized with S RAD initialized with S scRAD scRAD scRAD Sample number 2 4 8 2 4 8 2 4 8 Gene Expression MSE 0.41 0.28 0.37 0.31 0.27 0.37 0.22 0.15 0.13 Mixture fraction MSE 0.58 0.82 0.59 0.39 0.83 0.58 0.19 0.20 0.22 Citation Format: Haoyun Lei, Xiaoyan A. Guo, Yifeng Tao, Kai Ding, Xuecong Fu, Steffi Oesterreich, Adrian V. Lee, Russell Schwartz. Improved deconvolution of combined bulk and single-cell RNA-sequencing data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5031.
Abstract 6071: Activation of NOTCH signaling via DLL1 is mediated by APE1-redox-dependent NF-κB activation in esophageal adenocarcinoma
Authors: Lei Chen, Heng Lu, Dunfa Peng, Longlong Cao, Zheng Chen, Ajaz Bhat, Alexander Zaika, Shutian Zhang, Wael El-Rifai
Journal: Cancer Research (2022)

Abstract Esophageal adenocarcinoma (EAC) is one of the most lethal of all human malignancies. EAC arises in the setting of Barrett’s esophagus, which is an intestinal metaplastic precursor lesion that develops from chronic reflux of gastrointestinal contents (especially acidic bile salts). Here we report that NOTCH signaling is activated in the esophagus through a unique pathway during exposure to acidic bile salts and progression to EAC. Using a combination of public databases, EAC cell line models, transgenic mice, and patient tissue samples, we detected significant upregulation of several NOTCH signaling components in EAC. Activated NOTCH signaling was confirmed by nuclear accumulation of NOTCH1 cleaved fragment (NICD) with corresponding up-regulation of NOTCH targets in EAC cells in response to acidic bile salts. Moreover, we identified DLL1 as the predominant ligand contributing NOTCH1 activation. Remarkably, DLL1 was regulated by direct cross talk between redox and inflammatory pathways that are activated during both reflux and malignant transformation. Mechanistically, the APE1 redox function transcriptionally up-regulated NF-κB in response to bile salts. This licensed NF-κB to transcriptionally up-regulate DLL1 to activate and stimulate downstream NOTCH1 signaling, thereby defining a novel APE1-NF-kB-NOTCH pro-tumorigenic pathway. This pathway was important for maintaining tumor initiating (cancer “stem cell-like”) properties in vitro, recurrently detected in genetically engineered mouse models of EAC and in EAC patient samples in vivo, and portended an overall poor prognosis. Collectively, these findings indicate that progression from chronic injury to malignancy in the esophagus is driven by a unique mechanism that links redox balance, inflammation, embryonic development (NOTCH) together into a common pro-tumorigenic pathway that is intrinsic to EAC cells. Citation Format: Lei Chen, Heng Lu, Dunfa Peng, Longlong Cao, Zheng Chen, Ajaz Bhat, Alexander Zaika, Shutian Zhang, Wael El-Rifai. Activation of NOTCH signaling via DLL1 is mediated by APE1-redox-dependent NF-κB activation in esophageal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6071.
Abstract 1500: Exonuclease 1 recruitment in human DNA mismatch repair
Authors: Breanna Knicely
Journal: Cancer Research (2022)

Abstract DNA repair is the process by which cells identify and correct mutations present within the genome. These correction mechanisms maintain genomic stability and prevent the development of cancer. The DNA mismatch repair (MMR) pathway identifies and corrects small insertions, deletions, and misincorporations that arise within the genome as a result of errors during DNA replication. The process by which MMR corrects these mispairs includes recognition of the mispair by the MutS complex, recruitment of the MutL complex to the mutation site, excision of the mispair, and gap filling by DNA polymerase. MMR is also critical for inducing apoptosis after chemically induced mispairs, such as those from alkylating agents. Exonuclease 1 is the protein responsible for the excision step of MMR. However, MMR can occur in the absence of Exo-1. Thus, MMR can be separated into two subpathways: Exo1-dependent MMR and Exo1-independent MMR. In Exo1-dependent MMR Exo-1 binds to both the MutS complex and MutL complex. The MutL interaction is facilitated by an MLH1 interaction peptide (MIP) box. We recently identified a Msh2 interaction peptide (SHIP) box in yeast Exo1. This project aims to understand how MIP and putative human SHIP box motifs influence human Exo1 recruitment to MMR processes. We have created mutations within the predicted binding domains of human Exo1. We observe changes in localization of Exo1-mutant proteins within the cell, suggesting that changes in the overall MMR process may be present. We also observe changes in MMR-mediated apoptotic response when a subset of Exo1-mutations are expressed in the presence of endogenous wildtype Exo1, indicating a potential for a dominant negative interaction. Our ongoing studies are expected to shed more light upon how the changes in these interactions may affect the human MMR process and overall genomic stability. Citation Format: Breanna Knicely. Exonuclease 1 recruitment in human DNA mismatch repair [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1500.
Abstract 5682: Accelerated biological age is a driver of cancer susceptibility in genetic high risk breast tissue
Authors: Masaru Miyano, Sundus Shalabi, Rosalyn W. Sayaman, Martha Stampfer, Victoria E. Seewaldt, Mark A. LaBarge
Journal: Cancer Research (2022)

Abstract During aging in the human mammary gland, luminal epithelial cells lose lineage fidelity by expressing markers normally expressed in myoepithelial cells. We hypothesize that loss of lineage fidelity is a general manifestation of epithelia that are susceptible to cancer initiation. We show that histologically normal breast tissue from younger women who are susceptible to breast cancer because they harbor a germline mutation in BRCA1, BRCA2, or PALB2 genes, exhibit hallmarks of accelerated aging. These include proportionately increased luminal epithelial cells that acquired myoepithelial markers, decreased proportions of myoepithelial cells, and a basal differentiation bias or failure of differentiation of cKit+ progenitors. High-risk luminal and myoepithelial cells are transcriptionally enriched for genes of the opposite lineage, inflammatory, and cancer-related pathways. Genetically high risk luminal epithelial cells also show evidence of accelerated age, by as much as four decades compared to their chronological age, using a breast specific biological clock comprised of measurements of methylation and expression of the luminal-specific ELF5 transcription factor. We have identified breast aging hallmarks that reflect a convergent biology of cancer susceptibility, regardless of the specific underlying genetic or age-dependent risk, or the associated breast cancer subtype. Citation Format: Masaru Miyano, Sundus Shalabi, Rosalyn W. Sayaman, Martha Stampfer, Victoria E. Seewaldt, Mark A. LaBarge. Accelerated biological age is a driver of cancer susceptibility in genetic high risk breast tissue [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5682.